Biodistribution of 111In- and 90Y-labeled DOTA and maleimidocysteineamido-DOTA conjugated to chimeric anticarcinoembryonic antigen antibody in xenograft-bearing nude mice: comparison of stable and chemically labile linker systems.
Biodistributions of two radiometal chelate conjugates of the human/murine chimeric anticarcinoembryonic antigen monoclonal antibody cT84.66 were obtained in nude mice bearing LS174T human colorectal carcinoma xenografts. Derivatives of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) were covalently attached to the antibody by a stable amide linkage and by a maleimidocysteineamido side chain (MC-DOTA) that has been shown to be chemically labile at physiological temperature and pH. Biodistributions of both 111In and 90Y labels were obtained in these studies. At common biodistribution time points, it was found that the 111In label had greater uptake in the liver than 90Y for both conjugates. No significant differences were found with respect to bone uptake of 90Y using either chelate. Blood curves were generally lower at comparable time points for MC-DOTA, indicative of faster clearance as compared to DOTA. Tumor uptake was high for both conjugates (57-68% ID/g at 48 h), with a longer tumor residence time in the case of the DOTA conjugate, probably a result of its longer blood circulation times. We conclude that bone uptake of 90Y would be minimal if either DOTA or MC-DOTA were used as the bifunctional chelator. This would imply preference for these macrocyclic ligands if radiation doses to the bone marrow would be considered to be dominated by skeletal uptakes. Alternatively, if bone marrow radiation dose is dominated by circulating antibody, the chemically labile linker system employed by the MC-DOTA conjugate offers the advantage of enhanced blood clearance.
Williams
L E
LE
Division of Diagnostic Radiology, City of Hope National Medical Center, Duarte, California 91010, USA. lwilliams@smtplink.coh.org
Lewis
M R
MR
Bebb
G G
GG
Clarke
K G
KG
Odom-Maryon
T L
TL
Shively
J E
JE
Raubitschek
A A
AA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001853:Bone Marrow / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002614:Chelating Agents / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000378:metabolism; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008301:Maleimides / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008301:Maleimides; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid